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Licochalcone A inhibits interferon-gamma-induced programmed death-ligand 1 in lung cancer cells
- Source :
- Phytomedicine. 80:153394
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Background Programmed death-ligand 1 (PD-L1), which can be induced by interferon-gamma (IFN-γ) in the tumor microenvironment, is a critical immune checkpoint in cancer immunotherapy. Natural products which reduce IFN-γ-induced PD-L1 might be exert immunotherapy effect. Licochalcone A (LCA), a natural compound derived from the root of Glycyrrhiza inflata Batalin. (Fabaceae), was found to interfere IFN-γ-induced PD-L1. Purpose The aim of this study is to further clarify the effect and the mechanism of LCA on inhibiting IFN-γ-induced PD-L1 in lung cancer cells. Methods The expression levels of PD-L1 were evaluated by flow cytometry, western blot and qRT-PCR. Click-iT protein synthesis assay and luciferase assay were used to identify the effect of LCA on protein synthesis. Jurkat T cell proliferation and apoptosis in the co-culture system were detected by flow cytometry. Flow cytometry was also applied to evaluate reactive oxygen species (ROS) generation. Results LCA downregulated IFN-γ-induced PD-L1 protein expression and membrane localization in human lung cancer cells, regardless of inhibiting PD-L1 mRNA level or promoting its protein degradation. LCA decreased apoptosis and proliferative inhibition of Jurkat T cells caused by IFN-γ-induced PD-L1-expressing in A549 cells in the co-culture system. Strikingly, LCA was verified as a protein synthesis inhibitor, which reduced both cap-dependent and -independent translation. LCA inhibited PD-L1 translation, likely due to inhibition of 4EBP1 phosphorylation (Ser 65) and activation of PERK-eIF2α pathway. Furthermore, LCA induced ROS generation in a time-dependent manner in lung cancer cells. N-acetyl-L-cysteine (NAC) not only revered ROS generation triggered by LCA but also restored IFN-γ-induced expression of PD-L1. Both the inhibition of 4EBP1 phosphorylation (Ser 65) and activation of PERK-eIF2α axis triggered by LCA was restored by co-treatment with NAC. Conclusion LCA abrogated IFN-γ-induced PD-L1 expression via ROS generation to abolish the protein translation, indicating that LCA has the potential to be applied in cancer immunotherapy.
- Subjects :
- Lung Neoplasms
Licochalcone A
T cell
Pharmaceutical Science
Apoptosis
Cell Cycle Proteins
Protein degradation
Jurkat cells
B7-H1 Antigen
Flow cytometry
Interferon-gamma
Jurkat Cells
03 medical and health sciences
chemistry.chemical_compound
Chalcones
0302 clinical medicine
Cell Line, Tumor
Drug Discovery
Tumor Microenvironment
medicine
Humans
Interferon gamma
Phosphorylation
Adaptor Proteins, Signal Transducing
Cell Proliferation
030304 developmental biology
Pharmacology
A549 cell
0303 health sciences
medicine.diagnostic_test
Chemistry
Antineoplastic Agents, Phytogenic
medicine.anatomical_structure
Complementary and alternative medicine
030220 oncology & carcinogenesis
Cancer research
Molecular Medicine
Tumor Escape
Reactive Oxygen Species
medicine.drug
Subjects
Details
- ISSN :
- 09447113
- Volume :
- 80
- Database :
- OpenAIRE
- Journal :
- Phytomedicine
- Accession number :
- edsair.doi.dedup.....ff4130d410cf4741b4f9c95a98256f29